2. Academic Validation
  3. Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate

Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate

  • Bioorg Med Chem Lett. 2017 Aug 1;27(15):3231-3237. doi: 10.1016/j.bmcl.2017.06.041.
Yongtao Li 1,  Qingxiang Guo 1,  Chao Zhang 2,  Zhi Huang 2,  Tianqi Wang 2,  Xin Wang 2,  Xiang Wang 2,  Guangwei Xu 2,  Yanhua Liu 2,  Shengyong Yang 3,  Yan Fan 4,  Rong Xiang 5
Affiliations

Affiliations

  • 1 School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China; Tianjin International S & T Cooperation Base, 94 Weijin Road, Tianjin 300071, China.
  • 2 School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
  • 3 Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
  • 4 School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China; International Collaborative Laboratory of Biomedicine of the Ministry of Education, 94 Weijin Road, Tianjin 300071, China. Electronic address: [email protected].
  • 5 School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China; 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin 300071, China. Electronic address: [email protected].
PMID: 28651979 DOI: 10.1016/j.bmcl.2017.06.041
Abstract

A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC50=12nM. It effectively induced Apoptosis in breast and lung Cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of Cancer cells. Mice bared-breast Cancer treated with compound 4d showed significant suppression of Cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application.

Keywords

CDK9; Cancer; Inhibitor; LEE011.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-102039
    99.65%, CDK Inhibitor
    CDK